Highly acidic cation exchange resin containing amprotropine cations



United States Patent HIGHLY ACIBIC Cz iTiN EXQHANGE RESIN CONTAINING AIEEPROTRGPINE CATEONS Eugene Howard Gans, Belleviile, N.J., assignar to Hoffmann-La Roche ind, Nutiey, NJ a corporation of New Jersey No Drawing. Filed Oct. 31, 1960, Ser. No. 65,902

7 Claims. (Cl. 167-55) This invention relates to novel compositions of matter, useful as pharmaceuticals and as ingredients of particular pharmaceutical compositions. More especially, it relates to compositions of matter containing amprotropine, but which do not taste unpleasantly bitter in the manner of prior art compositions containing amprotropine.

Amprotropine, in the form of its salt with phosphoric acid (i.e. the phosphate of dl-tropic acid ester of 3-diethylamino-2,2-dimethyl-l-propanol), is a well known parasympatholytic agent, which has been employed for many years as active ingredient in prior art formulations marketed as antispasmodics; and to a limited extent, also as an antispasmodic ingredient in antacid tablets. Amprotropine phosphate, the material employed commercially, is an extremely bitter-tasting substance, and this characteristic has limited the extent to which it could be incorporated in pharmaceutical formulations adapted for relatively prolonged or slow oral ingestion, e.g. by chewing, sucking, sipping or the like. Thus, for example, while it has previously been desired to incorporate amprotropine phosphate in antacid tablets, in a proportion sufiicient to constitute an eifective antispasmodic dose, the bitter taste of this substance rendered it impossible to use more than a trifling (and indeed, therapeutically ineffective) dose per tablet; because of the extremely unpleasant sensation experienced by those consumers of the antacid tablets who chewed or sucked the latter.

It is an object of the present invention to provide amprotropine in a pharmaceutically acceptable, stable, non-bitter-tasting form, suitable for incorporation in pharmaceutical compositions adapted for slow or prolonged oral ingestion.

This object of the invention has been attained by the provision of the novel compositions of the invention; which can be broadly described, as to an essential characteristic thereof, as comprising a highly acidic cation exchange resin wherein at least some of the cations present are cations of amprotropine, i.e. cations of the formula Suitable ion exchange resins for practicing the invention are typified particularly by highly acidic polymerized vinylbenzene-containing nuclear sultonic acid cation exchange resins, as disclosed for example in U.S. Patent No. 2,366,007. Such resins, in a pharmaceutically acceptable, micro-powder form (i.e. of a size such that 95 percent of the material passes through a 325 mesh screen, U5. standard sieve series) me especially useful for purposes of the present invention, and are commercially available from the Rohm & Haas Co., Philadelphia, Pa., under their proprietary designation Amberlite XE-69. However, the invention is not restricted by the source or specific characteristics of the cation exchange material employed, otherwise than as limited by the claims herein; since it will be obvious to those skilled in the art that other resins, equivalent to the Amberlite XE-69 referred to herein, can be employed if desired.

The bulk amprotropine-resin compositions of the in- 3,131,121 Patented Apr. 28, 1964 "ice vention can be made conveniently by charging an aqueous solution of an amprotropine salt to a desired quantity of the highly acidic cation exchange resin. It is usually convenient to employ the cation exchange resin in its alkali metal cycle; for example, Amberlite XE-69 is supplied commercially in the sodium cycle, and is advantageously used in this form; however, if desired, the exchanger resin can be reacted when it is wholly or in part in its hydrogen cycle. Similarly, since amprotropine is conveniently available in the form of its addition salt with orthophosphoric acid, it is advantageous to employ amprotropine phosphate as a starting material in the processes of the invention; but the use of other acid addition salts, especially water-soluble mineral acid addition salts, is obviously within the purview of the invention. A satisfactory procedure for preparing the compositions of the invention comprises agitating an aqueous solution of amprotropine phosphate with the cation exchange resin in its sodium cycle, at room temperature, until the reaction mixture has reached equilibrium. Elevated temperatures can be employed, but ordinarily there is no advantage in operating at a temperature above about 50 C., and usually it is preferred to eifect the exchange reaction at room temperature, i.e. without external heating. In order to obtain a fairly high concentration of active ingredient in the amprotropine-loaded resin, it is usually desirable to continue the agitation until the concentration of amprotropine in the resin reaches at least 25 percent by weight. Ordinarily, it is preferred to allow the exchange reaction to go to equilibrium, and to reach a concentration of amprotropine in the resin of from about 34 percent to about 38 percent by weight.

After the cation exchanger has been loaded with amprotropine, the reaction mixture is filtered and the loaded resin is dried, e.g. in an oven at 45 C., or by exposure to a dry atmosphere at room temperature. Any agglomerations or lumps in the product can be broken up by grinding the dried product in a mill.

A preferred procedure for making the amprotropineresin products of the invention, in bulk form, comprises thoroughly agitating, at room temperature and for a period of several hours (eg from five to ten hours), a desired quantity of Amberlite XE-69 resin (micropowder, all in sodium cycle) with an aqueous solution of amprotropine phosphate, containing about 2.0 millimols of amprotropine phosphate per gram of resin dissolved in a quantity of Water equal to about 20 times the Weight of the resin. After completion of the reaction, the loaded resin is separated and preferably dried in an oven at 45 C. for about three days, and ground in a mill, if neces sary. The product is thus obtained in the form of a line, free-flowing, amorphous powder; stable and pleasanttasting.

The amprotropine-containing powder can be incorporated in liquid or solid pharmaceutical dosage forms, by methods known per se; and such pharmaceutical formulations, based on the amprotropine-loaded resins, constitute ancillary aspects of the present invention. Such dosage forms, containing amprotropine-resin powders as described above as an active ingredient, are particularly adapted for slow oral ingestion, as by chewing, sucking or sipping. In contract to bitter-tasting dosage forms of high amprotropine content hitherto available, the formulations of the present invention are tasteless in the sense that they do not give rise to the bitter taste sensation characteristic of amprotropine.

The invention is further disclosed in the following examples, which are illustrative but not limitative thereof.

Example 1 Dissolve 810 g. of amprotropine phosphate in 20 l. of deionized water. To the solution add 1 kg. of Amberlite XE69 resin, pharmaceutical grade, micro-form (finer than 325 mesh), sodium cycle. Stir the suspension well for 6 hours at 25 C. Filter the mixture through a centrifugal filter (whiz-bag type). Wash the cake with l. of deionized water. Dry the washed cake in an oven at 45 C. for 72 hours. Pass the dry resin through a Fitzpatrick mill to break up lumps formed during drying.

The product is a fine, amorphous, stable, pleasanttasting power containing 30.7 percent by Weight of amprotropine.

Example2 To 50 g. of amprotropine phosphate di solved in 250 cc. of water, add 30 cc. of 25 percent aqueous sodium hydroxide solution and 300 cc. of chloroform. Extract amprotropine based into the chloroform layer by shaking for 15 minutes. Remove the chloroform layer, and extract the base therefrom by shaking the chloroform layer with 300 cc. of deionized Water containing HCl equivalent to the amprotropine base plus 5 percent excess. Discard the chloroform layer. Filter the aqueous layer, adjust pH to 4.5 (approximately the pH of amprotropine hydrochloride) by adding NaOH solution, and add deionized Water to make up the total volume to 1500 cc. This solution contains 37.9 g. of arnprotropine base, in the form of its hydrochloride.

Add 60 g. of Amberlite XE69 resin (pharmaceutical grade, micro form, all in sodium cycle) to the above 1500 cc. of amprotropine hydrochloride solution. Stir well for one hour. Filter o11 the amprotIopine-loaded resin, and wash with one liter of water. Dry at 45 C. for 72 hours, and mill. The product is similar to that obtained in Example 1, but contains 29.6 percent by weight of amprotropine.

Example 3 Agitate 100 g. of Amberlite XE69 resin, of the same type employed in Examples 1 and 2, with 1000 cc. of 0.05 N aqueous HCl. Filter oil the resin, wash with 500 cc. of deionized water, and dry at 45 C. for 72 hours. This processing puts a portion of the resin in the hydrogen cycle.

To a solution of 50 g. of amprotropine phosphate in 250 cc. of water, add 25 cc. of 25 percent NaOH and 300 cc. of chloroform. Shake the mixture in a separatory funnel for 15 minutes and remove the chloroform layer containing amprotropine base. Wash the chloroform layer with water or slightly acidified Water until the wash water pH is 8.0 or lower. Fifty cc. of chloroform solution contains 6.3 g. of amprotropine base.

Stir g. of the above-processed Amberlite XE-69 resin (partially converted to the hydrogen cycle) with 50 cc. of the above described chloroform solution of amprotropine, for 30 minutes. Filter ofif the amprotropineloaded resin, and wash with chloroform. Dry the washed resin at 45 C. for 24 hours. The amprotropine resin product is similar to that of Example 1, but contains 34.9 percent by weight of amprotropine.

Example 4 Agitate 120 g. of Amberlite XE69 resin, same ldnd as used in Example 1, with a solution of 100 g. of amprotropine phosphate in 3 l. of water, for 1 hour at 25 C. Filter Off the amprotropine-containing resin, and wash with one liter of water. Dry the washer resin at 45 C. for 72 hours. The product is similar to that of Example 1, but contains 25.9 percent by weight of amprotropine.

Example 5 Exactly similar to Example 4, except that the suspension is stirred for 1 hour at 45 C., and the final product contains 25.6 percent by weight of amprotropine.

Example 6 Granulate a mixture of 180 g. of aluminum hydroxide; 320 g. of magnesium trisilicate; 30 g. of corn starch; 200 g. of mannitol; and 65 g. of sucrose with a 40% sucrose solution. After drying at 45 C. for 48 hours and grinding through a No. 16 mesh screen, add 24.7 g. of amprotropine-Amberlite XE-69 resin containing 30.7 percent by Weight of amprotropine (that described in Example 1); 10 g. of magnesium stearate; and 10 g. of powdered peppermint flavor. Mix well and compress into one thousand tablets, for use as an antacid.

Example 7 Exactly similar to Example 6, except that 61.9 g. of the same amprotropine-containing resin is used as the antispasmodic ingredient.

Example 8 Exactly similar to Example 6, except that 10 g. of phenindamine tartrate is added to the granulation as an anti-allergenic ingredient.

Example 9 Granulate a mixture of 500 g. of dihydroxy aluminum aminoacetate; 30 g. of corn starch; 200 g. of mannitol; 3.7 g. of sodium Sucaryl; and 65 g. of sucrose with a 40% solution of sucrose. After drying at 45 C. for 48 hours and grinding through a No. 16 screen, add 24.7 g. of amprotropine-Amberlite XE-69 resin containing 30.7 percent by weight of amprotropine (that described in Example 1); 10 g. of magnesium stearate; and 10 g. of

powdered peppermint flavor. Mix well and compress into one thousand tablets, for use as an antacid.

Example 10 Exactly similar to Example 9, except that 15 g. of phenobarbitol is added to the granulation, as a sedative ingredient; and 61.9 g. of the same amprotropine-containing resin is used as the antispasmodic ingredient.

Example 11 Example 12 Exactly similar to Example 11, except that 15 g. of phenobarbitol is added to the granulation, as a sedative ingredient.

Example 13 Granulate a mixture of 224 g. of acetylsalicylic acid; 160 g. of acetophenetidin; 30 g. of caffeine; and g. of 4X sucrose with 15% corn starch paste. After drying at 45 C. for 48 hours and grinding-through a No. 16 mesh screen, add 24.7 g. of amprotropine-Amberlite XE69 resin containing 30.7 percent by weight of amprotropine (described in Example 1); 10 g. of talc; and 10 gm. of Sterotex lubricant. Mix well and compress into one thousand tablets, for use as an analgesic.

Example 14 Exactly similar to Example 13, except that 10 g. of phenindamine tar'trate is added to the granulation, as an anti-allergenic ingredient.

Example 15 Exactly similar to Example 13, except that 10 g. of phenindamine tartrate, an anti-allergenic, and 5 g. of phenylephrine hydrochloride, a decongestant, are added to the granulation, to prepare one thousand analgesic or cold tablets.

Example 16 Granulate a mixture of g. of dihydroxy aluminum aminoacetate; 3 g. of sodium Sucaryl and 30 g. of corn starch with a solution of 40% sucrose, and dry at 45 C.

for 48 hours. Granulate 320 g. of acetylsalicylic acid with 15% corn starch paste and dry at 45 C. for 48 hours. After grinding both granulates through a No. 16 mesh screen, blend them together and add 24.7 g. of amprotropine-Amberlite XE-69 resin containing 30.7 percent by weight of amprotropine (described in Example 1); 10 g. of talc and 10 g. of Sterotex lubricant. Mix well and compress into one thousand buffered analgesic tablets.

Example 17 Granulate a mixture of 250 g. of acetophenetidin; 150 g. of isopropyl-antipyrine; 50 g. of cafieine; g. of sodium Sucaryl; 30 g. of corn starch; and 40 g. of 4X sucrose with a 30% ethanol solution of Carbowax 6000, and dry at 45 C. for 48 hours. Granulate a mixture of 30 g. of methyprylon; 50 g. of calcium silicate; and g. of corn starch with a 5% solution of methylcellulose (100 cps.), and dry at 45 C. for 48 hours. After grinding both granulates through a No. 16 mesh screen, blend them together and add 24.7 g. of amprotropine-Arnberlite XE- 69 resin containing 30.7 percent by weight of ammotropine (described in Example 1); 10 g. of talc and 10 g. of magnesium stearate. Mix well and compress into one thousand tablets, for use as an analgesic.

I claim:

1. As a substantially tasteless composition of matter, a highly acidic cation exchange resin wherein at least some of the cations present are cations of amprotropine.

2. As a substantially tasteless composition of matter, a pharmaceutically acceptable nuclear sulfonic acid cation exchange resin wherein at least a substantial proportion of the cations present are cations of amprotropine.

3. As a substantially tasteless composition of matter, a pharmaceutically acceptable, micro-powder, highly acidic polymerized vinylbenzene-containing nuclear sulfonic acid cation exchange resin containing amprotropine cations to a extent of at least about 25 percent amprotropine by Weight of said composition.

4. A pharmaceutical composition of matter adapted for slow oral ingestion comprising pharmaceutical adjuvant material in admixture with the composition of claim 3.

5. As a substantially tasteless composition of matter, a pharmaceutically acceptable, micro-powder, highly acidic polymerized vinylbenzene-containing nuclear sulfonic acid cation exchange resin containing amprotropine cations to an extent of from about 30 percent to about 38 percent amprotropine by weight of said composition.

6. An antacid composition containing acid-neutralizing ingredients in admixture with the composition of claim 5.

7. An analgesic composition containing analgesic ingredients in admixture with the composition of claim 5.

References Cited in the file of this patent FOREIGN PATENTS 22,281 Ireland Sept. 23, 1959 OTHER REFERENCES Abrahams: The Lancet, Dec. 28, 1957, pp. 1317-8.

American Drug Index, I. B. Lippincott, Philadelphia, Pa., 1958, page 585.

Becker: Toxicology and Applied Pharm. 1: 1, January 1959, pp. 42-54. 

1. AS A SUBSTANTIALLY TASTELESS COMPOSITON OF MATTER, A HIGHLY ACIDIC CATION EXCHANGE RESIN WHEREIN AT LEAST SOME OF THE CATIONS PRESENT ARE CATIONS OF AMPROTROPINE. 